Journal of the American College of Cardiology
© 2010 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 56, No. 10, 2010
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2010.02.066
QUARTERLY FOCUS ISSUE: HEART RHYTHM DISORDERS
Does Elevated C-Reactive Protein
Increase Atrial Fibrillation Risk?
A Mendelian Randomization of 47,000 Individuals
From the General Population
Sarah C. W. Marott, MD,*†‡ Børge G. Nordestgaard, MD, DMSC,*†‡§
Jeppe Zacho, MD,*†‡ Jens Friberg, MD, PHD,‡储 Gorm B. Jensen, MD, DMSC,‡§储
Anne Tybjærg-Hansen, MD, DMSC,†‡§¶ Marianne Benn, MD, PHD*†‡§
Herlev and Copenhagen, Denmark
Objectives
The purpose of this study was to test whether the association of C-reactive protein (CRP) with increased risk of
atrial fibrillation is a robust and perhaps even causal association.
Background
Elevated levels of CRP previously have been associated with increased risk of atrial fibrillation.
Methods
We studied 10,276 individuals from the prospective Copenhagen City Heart Study, including 771 individuals who
had atrial fibrillation during follow-up, and another 36,600 persons from the cross-sectional Copenhagen General Population Study, including 1,340 cases with atrial fibrillation. Individuals were genotyped for 4 CRP gene
polymorphisms and had high-sensitivity CRP levels measured.
Results
A CRP level in the upper versus lower quintile associated with a 2.19-fold (95% confidence interval [CI]: 1.54- to
3.10-fold) increased risk of atrial fibrillation. Risk estimates attenuated slightly after multifactorial adjustment to
1.77 (95% CI: 1.22 to 2.55), and after additional adjustment for heart failure and plasma fibrinogen level to
1.47 (95% CI: 1.02 to 2.13) and 1.63 (95% CI: 1.21 to 2.20), respectively. Genotype combinations of the 4 CRP
polymorphisms associated with up to a 63% increase in plasma CRP levels (p ⬍ 0.001), but not with increased
risk of atrial fibrillation. The estimated causal odds ratio for atrial fibrillation by instrumental variable analysis for
a doubling in genetically elevated CRP levels was lower than the odds ratio for atrial fibrillation observed for a
doubling in plasma CRP on logistic regression (0.94 [95% CI: 0.70 to 1.27] vs. 1.36 [95% CI: 1.30 to 1.44];
p ⬍ 0.001).
Conclusions
Elevated plasma CRP robustly associated with increased risk of atrial fibrillation; however, genetically elevated
CRP levels did not. This suggests that elevated plasma CRP per se does not increase atrial fibrillation risk.
(J Am Coll Cardiol 2010;56:789–95) © 2010 by the American College of Cardiology Foundation
Elevated levels of C-reactive protein (CRP) have been
suggested as a possible contributing factor to the initiation
or maintenance of atrial fibrillation. However, whether
increased plasma CRP levels are simply a marker for atrial
From the *Department of Clinical Biochemistry, Herlev Hospital, Copenhagen
University Hospital, Herlev, Denmark, †The Copenhagen General Population Study,
Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; ‡Faculty of
Health Sciences, University of Copenhagen, Copenhagen, Denmark; §The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital,
Copenhagen, Denmark; 储Department of Medicine, Hvidovre Hospital, Copenhagen
University Hospital, Copenhagen, Denmark; and the ¶Department of Clinical
Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen,
Denmark. This work was supported by The Danish Heart Foundation, a nonprofit
organization with no rights to approve or disapprove of the paper. The authors have
reported that they have no relationships to disclose.
Manuscript received October 7, 2009; revised manuscript received February 11,
2010, accepted February 25, 2010.
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fibrillation or whether elevated CRP actually contributes
directly to causing the disorder presently is unknown (1,2).
This question has clinical importance because several cardiovascular drugs, such as angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers, modulate the
inflammatory process in the heart (3,4), and because drugs
that specifically lower CRP levels already are being developed for treatment of cardiovascular disease (5).
Cause-and-effect relationships such as the one suggested
between plasma CRP levels and risk of atrial fibrillation can
be studied using an approach called Mendelian randomization (6). This approach uses genetic variants randomly
assorted during gamete formation and associated with levels
of plasma CRP to test whether there could be a causal
association between elevated plasma CRP levels and increased risk of atrial fibrillation. Thus, genetic variants that
790
Marott et al.
Elevated CRP and Atrial Fibrillation
JACC Vol. 56, No. 10, 2010
August 31, 2010:789–95
specifically increase plasma levels
of CRP (7) can be used as instruments to assess the consequences
CI ⴝ confidence interval
of lifelong high CRP levels indeCRP ⴝ C-reactive protein
pendently of other risk factors
OR ⴝ odds ratio
and not hampered by reverse
LDL ⴝ low-density
causation (8).
lipoprotein
We tested the hypothesis that
there is a robust and potential
causal association between elevated CRP levels and increased risk of atrial fibrillation. Robustness was tested by
adjustment of risk estimates for age, sex, and statin use; age,
sex, statin use, and CRP genotype; multifactorially for age,
sex, statin use, low-density lipoprotein (LDL) cholesterol,
body mass index, smoking, heavy drinking, diabetes mellitus, hypertension, and hyperthyroidism; multifactorially including heart failure, AGT-20A¡C, AGT T174M, and
ACE insertion or deletion genotypes; or finally, including
Abbreviations
and Acronyms
plasma fibrinogen. Potential causality was tested by examining whether CRP genotype combinations associated with
an increased risk of atrial fibrillation consistent with their
life-long elevation of plasma CRP levels.
Methods
For full information on study populations, genotyping and
biochemical analyses, covariates, and statistical analyses, please
refer to Supplementary Methods. The CCHS (Copenhagen
City Heart Study) is a prospective study of the Danish general
population initiated from 1976 through 1978 with follow-up
examinations in 1981 through 1983, 1991 through 1994, and
2001 through 2003 (9). The CGPS (Copenhagen General
Population Study) is a cross-sectional study initiated in 2003
with ongoing inclusion. Participants were ascertained exactly as
in the CCHS. All participants were white and of Danish
Characteristics
of IndividualsofinIndividuals
the 2 General
Population
by Plasma
Quintiles
Table 1
Characteristics
in the
2 GeneralStudies
Population
StudiesCRP
by Plasma
CRP Quintiles
Quintiles of Plasma CRP
1
2
3
4
5
p Value
1.0 (0.1–1.2)
1.3 (1.2–1.5)
1.7 (1.5–2.1)
2.7 (2.1–3.6)
9.9 (3.6–103)
⬍0.001
Copenhagen City Heart Study
CRP (mg/dl)
No. of individuals
Women
Age (yrs)
Statin use
1,656
47
50 (37–63)
0.5
1,657
56
57 (44–68)
0.8
1,654
58
61 (50–70)
0.9
1,654
55
64 (53–72)
1.2
1,655
56
64 (55–72)
0.2
LDL cholesterol (mmol/l)
3.3 (2.7–4.1)
3.6 (2.9–4.3)
3.8 (3.1–4.5)
3.8 (3.1–4.7)
3.7 (3.0–4.5)
Body mass index (kg/m2)
23 (21–25)
24 (22–27)
25 (23–28)
26 (24–29)
27 (24–30)
Smoking, active and former
51
56
60
Heavy drinkers
10
10
2
3
Diabetes mellitus
Hypertension
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
66
69
10
9
10
0.52
3
5
8
⬍0.001
⬍0.001
38
48
57
65
65
Hyperthyroidism
2
2
2
2
3
0.06
Heart failure
4
7
10
15
19
⬍0.001
2.5 (2.1–2.9)
2.7 (2.3–3.1)
2.9 (2.5–3.4)
3.2 (2.8–3.7)
3.8 (3.2–4.5)
⬍0.001
AGT-29 A¡C (AA/AC/CC)
70/27/3
70/27/3
72/26/2
72/25/3
70/28/2
0.71
AGT T174M (TT/TM/MM)
77/22/2
76/23/2
79/19/1
77/21/2
77/21/1
0.29
ACE ins/del (dd/id/ii)
26/50/24
26/49/24
26/50/24
26/48/25
25/51/24
0.56
0.5 (0.01–0.8)
1.1 (0.8–1.3)
1.5 (1.3–1.9)
2.5 (1.9–3.4)
8.7 (3.4–330)
⬍0.001
Fibrinogen (mg/l)
Copenhagen General Population Study
CRP (mg/dl)
No. of individuals
Women
Age (yrs)
Statin use
7,331
53
53 (45–63)
52
58 (48–66)
7,316
53
59 (49–67)
7,315
52
60 (50–69)
7,318
57
62 (51–71)
⬍0.001
10
11
11
3.1 (2.2–3.7)
3.1 (2.5–3.8)
3.2 (2.6–3.9)
3.3 (2.7–4.0)
3.3 (2.6–3.9)
⬍0.001
Body mass index (kg/m2)
24 (24–26)
25 (23–27)
26 (23–28)
27 (24–30)
28 (25–31)
⬍0.001
Heavy drinkers
11
⬍0.001
⬍0.001
LDL cholesterol (mmol/l)
Smoking, active and former
6
7,320
55
45
39
49
58
0.12
2
3
3
3
3
0.02
2
3
3
4
6
⬍0.001
55
63
67
72
77
⬍0.001
Hyperthyroidism
1
1
1
1
2
0.02
Heart failure
1
1
1
2
4
⬍0.001
Diabetes mellitus
Hypertension
Fibrinogen (mg/l)
1.0 (0.9–1.2)
1.1 (1.0–1.2)
1.2 (1.0–1.3)
1.3 (1.1–1.4)
1.4 (1.2–1.7)
⬍0.001
Continuous values are summarized as median (interquartile range); p value is for trend among quintiles by a nonparametric test by Cuzick. Categorical values are summarized in percent; p values for trend
by Cuzick’s extension of a Wilcoxon rank-sum test.
CRP ⫽ C-reactive protein; LDL ⫽ low-density lipoprotein.
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JACC Vol. 56, No. 10, 2010
August 31, 2010:789–95
descent. No individuals were included in both populations, and
follow-up was 100% complete.
Results
Characteristics of participants in each study cohort are
shown in Table 1 as a function of quintiles of plasma CRP.
In each cohort, increasing plasma CRP levels associated
with female sex, increasing age, plasma LDL cholesterol,
body mass index, and fibrinogen levels and with presence of
statin use, smoking, diabetes mellitus, hypertension, and
heart failure (all p ⬍ 0.001 for trend) (Table 1). Levels of
plasma CRP did not associate with distribution of AGT or
ACE genotype (Table 1).
Plasma CRP and risk of atrial fibrillation. Increasing
levels of plasma CRP were associated with increasing risk of
atrial fibrillation (Fig. 1). In the CCHS population, CRP in
the upper versus lower quintile was associated with a
2.19-fold (95% confidence interval [CI]: 1.54- to 3.10-fold)
increased risk of atrial fibrillation after adjustment for age,
Figure 1
Marott et al.
Elevated CRP and Atrial Fibrillation
791
sex, and statin use. The corresponding hazard ratio after
further adjustment for CRP genotype was 2.22 (95% CI:
1.55 to 3.16), and that after multifactorial adjustment was
1.77 (95% CI: 1.22 to 2.55). Similar results were seen in the
CGPS (Fig. 1).
Heart failure is one of the major risk factors for atrial
fibrillation, and including heart failure into the multifactorial model attenuated the risk of atrial fibrillation
associated with the plasma CRP level to 1.47 (95% CI:
1.02 to 2.13) for upper versus lower quintile in the
CCHS, and similarly in the CGPS (Fig. 2). Adjusting for
plasma fibrinogen level, another marker of inflammation,
attenuated the corresponding risk of atrial fibrillation to
1.63 (95% CI: 1.21 to 2.20) in the CCHS, and similarly
in the CGPS (Fig. 2).
CRP genotype and plasma CRP. In accordance with
previous findings (8), the CRP polymorphism rs1205 was
associated with lower plasma CRP levels, whereas the
rs1130864, rs3091244, and rs3093077 polymorphisms were
Risk of Atrial Fibrillation as a Function of Plasma Levels of CRP in the General Population
High-sensitivity plasma C-reactive protein (CRP) levels were measured in 10,276 individuals who participated in the 1991 through 1994 examination of The CCHS
(Copenhagen City Heart Study) (left panels) and subsequently were followed up for 12 to 15 years with respect to incident atrial fibrillation; individuals with atrial fibrillation before study entry were excluded. Findings were retested in 36,600 individuals from the cross-sectional CGPS (Copenhagen General Population Study) (right
panels). Multifactorial adjustment was for age, sex, statin use, low-density lipoprotein cholesterol, body mass index, smoking, heavy drinking, diabetes mellitus,
hypertension, hyperthyroidism, and AGT and ACE genotypes (CCHS only). CI ⫽ confidence interval.
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792
Figure 2
Marott et al.
Elevated CRP and Atrial Fibrillation
JACC Vol. 56, No. 10, 2010
August 31, 2010:789–95
Risk of Atrial Fibrillation as a Function of Plasma Levels of CRP in the
General Population, Additionally Adjusted for Heart Failure and Plasma Fibrinogen Levels
Robustness of the association of plasma CRP levels with risk of atrial fibrillation was tested by separately including adjustment of heart failure and plasma fibrinogen
levels into the multifactorially adjusted model from Figure 1. This was tested in 10,276 individuals who participated in the 1991 through 1994 examination of the CCHS
(left panels), and findings were retested in 36,600 individuals from the cross-sectional CGPS (right panels). Abbreviations as in Figure 1.
associated with higher CRP levels (Fig. 3). Combining
the genotypes resulted in up to a 63% difference in plasma
CRP levels between the lowest and highest levels among
the 9 most common genotype combinations. Contribution of genotype to variation in plasma CRP levels
estimated as partial r2 values ranged from 1.3% to 1.5%
for the different CRP genotypes or genotype combinations. Covariates (age, lipids, body mass index, alcohol
consumption, smoking, statin use, hypertension, diabetes, heart failure, and AGT and ACE genotype) did not
differ among the 9 different CRP genotypes (Supplementary Table) (8).
CRP genotype and risk of atrial fibrillation. Hazard
ratios for atrial fibrillation as a function of genotype in
the CCHS did not differ consistently from 1.0 for any of
the individual CRP polymorphisms, or for genotype
combinations (p ⫽ 0.12 to 0.70 for trend) (Fig. 4). These
findings were confirmed in the CGPS (p ⫽ 0.22 to 0.78
for trend). The various risk factors were distributed
equally among the different CRP genotype combinations
(Supplementary Table) (8). This also was true for each of
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the 4 genotypes separately and for genotype combinations
in each of the studies as previously reported (8).
Potential causal effect of CRP on the risk of atrial
fibrillation. Assuming that elevations in CRP levels have a
causal effect on risk of atrial fibrillation, genetically elevated
plasma CRP levels should confer a similar increase in
disease risk as that observed for elevated plasma CRP levels
encountered in the general populations. Based on this
assumption and to obtain maximal statistical power, we
estimated, using instrumental variable analysis by generalized least square regression, that a doubling of plasma CRP
levels resulting from CRP genotype combinations associated
with a causal odds ratio (OR) of 0.76 (95% CI: 0.62 to 0.93)
in the studies combined, contrasting the observed OR
associated with a doubling of plasma CRP levels of 1.12
(95% CI: 1.06 to 1.17) in the 2 studies combined (causal vs.
observed OR, p ⬍ 0.001). Similar results for unadjusted
analyses were for plasma CRP 1.36 (95% CI: 1.30 to 1.44)
and for genetically elevated CRP 0.94 (95% CI: 0.70 to
1.27) (causal vs. observed OR, p ⬍ 0.001) (Fig. 5).
JACC Vol. 56, No. 10, 2010
August 31, 2010:789–95
Figure 3
Marott et al.
Elevated CRP and Atrial Fibrillation
793
Plasma Levels of CRP as a Function of CRP Genotypes and Genotype Combinations
This was tested in 36,600 individuals from the general population, the CGPS. Partial r2 values were determined
after adjustment for variation in plasma CRP levels resulting from age, sex, and statin use. Abbreviations as in Figure 1.
Discussion
The main findings of this study are that elevated plasma
CRP levels are associated robustly with increased risk of
atrial fibrillation, but that genetically elevated CRP levels
are not. This suggests that elevated plasma CRP levels per
se do not increase atrial fibrillation risk.
The finding that increased plasma CRP levels associate
with an increased risk of atrial fibrillation is in accordance
with a previous prospective study (n ⫽ 5,806 including 897
events) (10) and with 3 case-control studies (n ⫽ 121, n ⫽
202, and n ⫽ 2,796, respectively) (1,11,12). Also, a previous
study from the CCHS showed that plasma fibrinogen,
another marker of inflammation, associated with risk of
atrial fibrillation (13). Importantly, in the present study, we
also showed that this association is robust, because estimates
only attenuated slightly when adjusting for CRP genotype,
multifactorially, and multifactorially including heart failure
and plasma fibrinogen.
During data analysis, we adjusted estimates of risk associated with plasma CRP levels for potential confounders
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such as LDL cholesterol, body mass index, smoking, heavy
drinking, diabetes mellitus, hypertension, hyperthyroidism,
and ACE and AGT genotypes and observed that the risk
estimates largely are not confounded by these factors.
Adjusting either for heart failure, a well-known risk factor
for atrial fibrillation associated with increased levels of
plasma CRP, or for fibrinogen, another marker of inflammation, somewhat attenuated the risk estimates, although
they remained significant, also suggesting that plasma CRP
levels robustly predict atrial fibrillation risk.
To study a cause-and-effect relationship such as the one
suggested between plasma CRP levels and risk of atrial
fibrillation, a Mendelian randomization approach can be
used to circumvent regression dilution bias, confounding,
and reverse causation, although, 3 conditions must be
fulfilled (14). First, CRP genotype (instrumental variable)
must be associated with the exposure variable (plasma
CRP). In the present study, CRP genotype combinations
contributed 1.5% to the total variation in plasma CRP, but
associated with up to a 63% increase in plasma CRP levels.
794
Figure 4
Marott et al.
Elevated CRP and Atrial Fibrillation
JACC Vol. 56, No. 10, 2010
August 31, 2010:789–95
Risk of Atrial Fibrillation as a Function of CRP Genotype and Genotype Combinations in the General Population
The hazard and odds ratios were adjusted multifactorially for age, sex, statin use, low-density lipoprotein cholesterol, body mass index, smoking, heavy drinking, diabetes mellitus, hypertension, hyperthyroidism, and AGT and ACE genotype (CCHS only). This was tested in 10,276 individuals who participated in the 1991 through 1994
examination of the CCHS (left panels), and findings were retested in 36,600 individuals from the cross-sectional CGPS (right panels). N.A. ⫽ not estimated because of
no events in GG genotype group; other abbreviations as in Figure 1.
A similar increase in nongenetic plasma CRP is associated
with a 7% increase in risk of atrial fibrillation (OR: 1.07;
95% CI: 1.04 to 1.10) (Fig. 5); thus, genotype combinations
associate with a sufficient increase in plasma CRP to serve
as instruments in a Mendelian randomization study.
Second, CRP genotype must be independent of factors
confounding the association of plasma CRP levels with risk
of atrial fibrillation, clearly fulfilled in the present studies
(Supplementary Table) (8). Finally, CRP genotype must be
independent of the outcome, that is, it must not affect risk
of atrial fibrillation by pathways other than plasma CRP,
given confounding factors (6,14). Having fulfilled these
requirements, comparison of the positive association between plasma CRP levels and the risk of atrial fibrillation
(OR per doubling: 1.12 [95% CI: 1.06 to 1.17]; unadjusted
OR: 1.36 [95% CI: 1.30 to 1.44]) with the association
between genetically elevated CRP levels and risk of atrial
fibrillation (OR: 0.76 [95% CI: 0.62 to 0.93]; unadjusted
OR: 0.94 [95% CI: 0.70 to 1.27]) showed a significant
contrast, not in favor of a causal relationship between
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elevated plasma CRP levels and increased atrial fibrillation
risk. However, because plasma CRP is a marker only of
inflammation, our study does not exclude a potential causal
association between inflammation and atrial fibrillation.
Study limitations. Potential limitations of this study include, as always, selection bias and misclassification of
plasma CRP levels, CRP genotype, and atrial fibrillation.
However, the study populations used were selected using
the national Danish Civil Registration system, drawing 2
random samples from the Danish adult general population without knowledge of plasma CRP levels, genotypes,
and diagnosis of atrial fibrillation, largely excluding
important selection bias. Some misclassification of
plasma markers like CRP is well known because of
regression dilution bias; however, we were able to correct
for this because CRP levels were measured twice in
approximately 6,300 individuals. Misclassification of genotype is unlikely in the present study, because genotypes
were controlled by sequencing and because overall call
rates were more than 99.9% as a result of repeated reruns.
Marott et al.
Elevated CRP and Atrial Fibrillation
JACC Vol. 56, No. 10, 2010
August 31, 2010:789–95
795
Acknowledgments
The authors thank Hanne Damm, Dorthe Uldall Andersen,
and Dorthe Kjeldgaard Hansen for assisting with the
large-scale genotyping, and the staff and participants of the
Copenhagen City Heart Study and the Copenhagen General Population Study for their important contributions.
Reprints requests and correspondence: Dr. Marianne Benn,
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev,
Denmark. E-mail: marben21@heh.regionh.dk.
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Figure 5
Studies Summary of the Causal Effect of CRP on
Risk of Atrial Fibrillation in the General Population
The causal effect of CRP on risk of atrial fibrillation was estimated by the association between genetically elevated CRP levels and risk of atrial fibrillation,
using instrumental variable analysis by generalized least square regression
(solid line). This risk is compared with the observed risk associated with
plasma CRP in the general population (dashed line). For comparison, risk estimates for a doubling (100% increase) in CRP levels are given. Estimates are
based on the combined studies with 10,276 individuals from the CCHS and
36,600 individuals from the CGPS. OR ⫽ odds ratio; other abbreviations as in
Figure 1.
Ascertainment and classification of atrial fibrillation is a
potential limitation of the present study because atrial
fibrillation may have occurred in some individuals without having been diagnosed, because atrial fibrillation may
have been coded incorrectly in the national Danish
Patient Registry, or because some individuals might not
have had atrial fibrillation at one of the follow-up
examinations, that is, if they had paroxystic atrial fibrillation. Misclassification of a diagnosis of atrial fibrillation
would result in an underestimation of the risk estimates,
and thus more conservative estimates for the association
of plasma CRP levels with risk of atrial fibrillation than
observed in the present study. Finally, information on
medication, that is, treatment with statin and antihypertensive medication, is self-reported and may be inaccurate. Such an inaccuracy tends to make association of
plasma CRP levels with risk of atrial fibrillation more
conservative, but would not influence the association of
CRP genotype with risk of atrial fibrillation.
Conclusions
Elevated plasma CRP was robustly associated with increased risk of atrial fibrillation, although genetically
elevated CRP levels were not. This suggests that elevated
plasma CRP per se does not increase atrial fibrillation
risk.
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Key Words: atrial fibrillation y C-reactive protein y genetics y
inflammation y Mendelian randomization.
APPENDIX
For a supplementary table and method section,
please see the online version of this article.